Promoter Structure

There are genetically defined enhancer elements (lethal I,II, and III) for expression of cut in individual cell types. These are located 38 kb upstream from the structural gene. Additional wing and femur enhancers are found 83 and 120 kb upstream of the structural gene. Analysis of the 38 kb region containing the three genetically defined enhancers reveals 8 separate DNA fragments that drive organ specific cut expression (Liu, 1991 and Jack, 1995).

One particular enhancer is responsible for cut activity at the wing margin, the boundary between dorsal and ventral wing compartments. When the gypsy retrotransposon of Drosophila inserts between an enhancer and a proximal promoter it prevents the enhancer from activating transcription. Enhancers are blocked because the protein (SUHW) encoded by the suppressor of Hairy-wing [su(Hw)] gene binds to gypsy. For example, gypsy insertions in an 85 kilobase region between a wing margin-specific enhancer and the promoter in the cut gene cause a cut wing phenotype that is suppressed by su(Hw) mutations. Enhancer-blocking by SUHW is reversible and that it occurs soon after binding of active SUHW to gypsy DNA. These results are consistent with models in which SUHW structurally interferes with enhancer-promoter interactions (Dorsett, 1993).

Chip may encode an enhancer-facilitator, acting to facilitate the activity of distal enhancers. The mechanisms allowing remote enhancers to regulate promoters several kilobase pairs away are unknown but are blocked by the Drosophila suppressor of Hairy-wing protein [su(Hw)] that binds to gypsy retrovirus insertions between enhancers and promoters. su(Hw) bound to a gypsy insertion in the cut gene also appears to act interchromosomally to antagonize enhancer-promoter interactions on the homologous chromosome when activity of the Chip gene is reduced. Chip is needed for the wing margin enhancer of cut. The Chip mutation dominantly enhances the mutant phenotypes displayed by partially suppressed gypsy insertions in both cut and Ultrabithorax and is a homozygous larval lethal, indicating that Chip regulates multiple genes. Chip is normally required for wing margin enhancer function of cut because Chip mutations also enhance the cut wing phenotype of a cut mutation and heterozygotes for Chip display cut wing phenotypes when either scalloped or mastermind (mam) are also heterozygous mutant. Both Sc and Mam are known to regulate the cut distal enhancer, but in contrast to sd and mam mutants, Chip mutants display stronger genetic interactions with gypsy insertions than with wing margin enhancer deletions. Thus, in a heterozygous Chip mutant, a heterozygous gypsy insertion in cut displays a cut wing phenotype, whereas a heterozygous enhancer deletion does not. Dependence on the nature of the heterozygous lesion in the regulatory region strongly suggests that Chip directly regulates cut. More strikingly, it indicates that in a Chip heterozygote, a gypsy insertion is more deleterious to enhancer function than deletion of the enhancer. The simplest explanation is that su(Hw) bound to gypsy in one cut allele acts in a transvection-like manner (interchromosomally) to block the wing enhancer in the wild-type cut allele on a second chromosome. This implicates Chip in enhancer-promoter communication (Morcillo, 1997 and references).

Chip was cloned and found to encode a homolog of the recently discovered mouse Nli/Ldb1/Clim-2 and Xenopus Xldb1 proteins, which bind nuclear LIM domain proteins. Chip protein interacts with the LIM domains in the Apterous homeodomain protein, and Chip interacts genetically with apterous, showing that these interactions are important for Apterous function in vivo. Importantly, Chip also appears to have broad functions beyond interactions with LIM domain proteins. Chip is a ubiquitous chromosomal factor required for normal expression of diverse genes at many stages of development. It is suggested that Chip cooperates with different LIM domain proteins and other factors to structurally support remote enhancer-promoter interactions (Morcillo, 1997).

The mechanisms that allow enhancers to activate promoters from thousands of base pairs away are disrupted by the Drosophila Suppressor of Hairy-wing protein (Su[Hw]). Su[Hw] binds a DNA sequence in the gypsy retrotransposon and prevents activation of promoter-enhancers that are distal to a gypsy insertion in a gene without affecting proximal promoter-enhancers. Several observations indicate that SUHW does not affect enhancer-binding activators. Instead, SUHW may interfere with factors that structurally facilitate interactions between an enhancer and promoter. To identify putative enhancer facilitators, a screen for mutations that reduce activity of the remote wing margin enhancer in the cut gene was performed. Mutations in scalloped, mastermind, and a previously unknown gene, Chip, were isolated. A TEA DNA-binding domain in the Scalloped protein binds the wing margin enhancer. Interactions among scalloped, mastermind and Chip mutations indicate that Mastermind and Chip act synergistically with Scalloped to regulate the wing margin enhancer. Chip is essential and also affects expression of a gypsy insertion in Ultrabithorax. Relative to mutations in either scalloped or mastermind, a Chip mutation hypersensitizes the wing margin enhancer in cut to gypsy insertions. Therefore, Chip might encode a target of su(Hw) enhancer-blocking activity (Morcillo, 1996).

Enhancers are able to activate promoters located several kilobases away, but how this is accomplished is not known. Activation by the wing margin enhancer in the cut gene, located 85 kb from the promoter, requires several genes that participate in the Notch receptor pathway in the wing margin, including scalloped, vestigial, mastermind, Chip, and the Nipped locus. Nipped mutations disrupt one or more of four essential complementation groups: l(2)41Ae, l(2)41Af, Nipped-A, and Nipped-B. Heterozygous Nipped mutations modify Notch mutant phenotypes in the wing margin and other tissues, and magnify the effects that mutations in the cis regulatory region of cut have on cut expression. Nipped-A and l(2)41Af mutations further diminish activation of a wing margin enhancer that has been partly impaired due to a small deletion. In contrast, Nipped-B mutations do not diminish activation by the impaired enhancer, but increase the inhibitory effect of a gypsy transposon insertion between the enhancer and promoter. Nipped-B mutations also magnify the effect of a gypsy insertion in the Ultrabithorax gene. Gypsy binds the Suppressor of Hairy-wing insulator protein [Su(Hw)] that blocks enhancer-promoter communication. Increased insulation by Su(Hw) in Nipped-B mutants suggests that Nipped-B products structurally facilitate enhancer-promoter communication. Compatible with this idea, Nipped-B protein is homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair (Rollins, 1999).

Database searches reveal homologs of the Nipped-B protein in fungi, worms, and mammals. Only short expressed-sequence tags (ESTs) of Caenorhabditis elegans, mouse, and humans were identified. The human ESTs are from a variety of tissue-specific libraries, suggesting that the human homologs are widely expressed. The combined human ESTs, which do not represent a complete sequence, encode 411 amino acids. Residues 2-232 of the partial human protein overlap Nipped-B residues 1744-1994 with 34% identity and 52% similarity. In order of decreasing homology, the 2157-amino acid Rad9 protein of Coprinus cinereus, the 1583-amino acid Mis4 protein of Schizosaccharomyces pombe, and the 1493-amino acid Scc2 protein of Saccharomyces cerevisiae, are more distantly related. Rad9 residues 669-2071 display 21% identity and 41% similarity to Nipped-B residues 576-1887; Mis4 residues 780-1492 have 19% identity and 41% similarity to Nipped-B residues 1110-1818, and Scc2 residues 697-1291 display 19% identity with 39% similarity to Nipped-B residues 1103-1704. The three fungal homologs show similar levels of homology among themselves, but it is evident that there is a large conserved domain shared by all three proteins. Consistent with the idea that Nipped-B plays an architectural role in enhancer-promoter communication, the fungal homologs of Nipped-B all participate in regulating chromosome structure, with roles in DNA repair, meiotic chromosome condensation, or sister chromatid cohesion. It has been proposed that these three fungal proteins define a new class of chromosomal proteins and have been named adherins to distinguish them from the cohesins that have similar functions (Rollins, 1999 and references).

Although the data do not yet distinguish whether the heterochromatic Nipped locus is a single complex transcription unit or a cluster of distinct genes, several conclusions may be drawn about Nipped functions and their roles relative to the other cut regulators. To summarize, Nipped mutations define three separable essential functions that regulate cut in the wing margin, provided by the Nipped-A, Nipped-B, and l(2)41Af lethal complementation groups. Dosage-sensitive genetic interactions indicate that Nipped-A and l(2)41Af cooperate closely with mam and vg in the regulation of cut. Similar to mam and unlike sd and vg, Nipped-A and l(2)41Af also modulate Notch receptor signaling or expression in multiple tissues. Nipped-B has the most unique function. Like Chip, Nipped-B regulates both cut and Ubx and is antagonistic to insulation by Su(Hw). Together, the antagonism to Su(Hw) and the homology to chromosomal adherins lead to a proposal that Nipped-B protein performs an architectural role in enhancer-promoter communication (Rollins, 1999).

The primary evidence that Nipped-B is antagonistic to Su(Hw) insulator activity is that Nipped-B activity is only strongly limiting for cut expression when there is a gypsy insertion between the wing margin enhancer and promoter. Strikingly, in contrast to mutations disrupting any of the other cut regulators (including sd, mam, Chip, vg, Nipped-A, and l(2)41Af), heterozygous Nipped-B mutations do not detectably reduce activation by the partially crippled wing margin enhancer in ct53d. Compared with sd, mam, or Nipped-A mutations, heterozygous Nipped-B mutations also only slightly reduce activation of cut expression by the solo wild-type wing margin enhancer present in ct2s heterozygotes. Therefore, with both ct53d and ct2s, Nipped-B products are less limiting for wing margin enhancer activity than are Nipped-A products. Remarkably, the opposite is true when there is a gypsy insulator insertion in cut. Heterozygous Nipped-B mutations are severalfold more effective than Nipped-A mutations in magnifying the effect of the Su(Hw) insulator in ctL-32; su(Hw)e2 flies. Furthermore, of the known cut regulators, only Chip and Nipped-B mutations magnify the effect of the Su(Hw) insulator in su(Hw)e2 bx34e flies. The antagonism between Nipped-B and Su(Hw) is unlikely to be specific to the Su(Hw)e2 protein. Su(Hw)e2 has an amino acid substitution in a zinc finger that reduces DNA-binding activity but contains a wild-type enhancer-blocking domain. Moreover, Nipped-B mutations also reduce cut expression in the absence of a gypsy insertion, indicating that the increased effectiveness of Su(Hw)e2 in Nipped-B mutants reflects a change in cut regulation rather than a change in Su(Hw)e2 protein activity (Rollins, 1999).

The available data are insufficient to determine with absolute certainty whether or not Nipped-B directly regulates cut. However, direct regulation provides the simplest explanation for several observations. The ability of Nipped-B mutations to exacerbate different cut mutant phenotypes differs from all other cut regulators such as sd, vg, and mam. Therefore, Nipped-B does not regulate cut indirectly by altering expression of any of the other known cut regulators. Moreover, the effects of the Nipped-B407 mutation on cut and Ubx mutant phenotypes are dominant, although Nipped-B407 only partially reduces Nipped-B mRNA levels. A partial loss of Nipped-B activity is unlikely to cause a similar or greater loss of activity of another cut regulator. Therefore, in light of the observation that Nipped-B mutations magnify insulation by gypsy insertions in both cut and Ubx, the idea that Nipped-B products directly support enhancer-promoter communication in cut and Ubx is strongly favored. Because Nipped-B is essential and Nipped-B mRNA is expressed at all developmental stages, it may play a similar role in other genes (Rollins, 1999).

The hypothesis that Nipped-B protein plays an architectural role to facilitate enhancer-promoter interactions in cut and Ubx is supported by the diverse effects that the fungal adherin homologs of the Nipped-B protein have on chromosome structure and function. The Rad9 protein of Coprinus was identified in a screen for radiation-sensitive mutants. rad9 mutants were subsequently observed to display defects in synaptonemal complex formation and chromosome condensation during meiosis. Mutations in the Scc2 gene of budding yeast were identified as lethal temperature-sensitive mutants that display defects in sister chromatid cohesion during mitosis. In scc2 mutants, sister chromatids separate prematurely, just after formation of the bipolar spindle. Mutations in the Mis4 gene of fission yeast were identified as temperature-sensitive lethal mutants that missegregate minichromosomes. mis4 mutants also missegregate regular chromosomes and are radiation sensitive. The Mis4 protein is required during S phase and associates with chromosomes during the entire cell cycle. These diverse mutant phenotypes indicate that adherins play fundamental roles in chromosome structure. Although it is not yet known if Nipped-B also participates in mitotic or meiotic chromosome structure, its homology to adherins suggests explanations for how Nipped-B could architecturally facilitate enhancer-promoter communication. It is tempting to speculate, for example, that the biochemical activity of Nipped-B is to recognize and stabilize chromatin loops that hold distant chromosomal sites closer together. The chromatin loops could be created by other factors involved in enhancer-promoter interactions (Rollins, 1999 and references).

Insulation of enhancer-promoter communication by a gypsy transposon insert in the Drosophila cut gene: Cooperation between Suppressor of Hairy-wing and Modifier of mdg4 proteins

The Drosophila mod(mdg4) gene products counteract heterochromatin-mediated silencing of the white gene and help activate genes of the bithorax complex. They also regulate the insulator activity of the gypsy transposon when gypsy inserts between an enhancer and promoter. The Su(Hw) protein is required for gypsy-mediated insulation, and the Mod(mdg4)-67.2 protein binds to Su(Hw). The aim of this study was to determine whether Mod(mdg4)-67.2 is a coinsulator that helps Su(Hw) block enhancers or a facilitator of activation that is inhibited by Su(Hw). Evidence is provided that Mod(mdg4)-67.2 acts as a coinsulator by showing that some loss-of-function mod(mdg4) mutations decrease enhancer blocking by a gypsy insert in the cut gene. The C terminus of Mod(mdg4)-67.2 binds in vitro to a region of Su(Hw) that is required for insulation, while the N terminus mediates self-association. The N terminus of Mod(mdg4)-67.2 also interacts with the Chip protein, which facilitates activation of cut. Mod(mdg4)-67.2 truncated in the C terminus interferes in a dominant-negative fashion with insulation in cut but does not significantly affect heterochromatin-mediated silencing of white. It is inferred that multiple contacts between Su(Hw) and a Mod(mdg4)-67.2 multimer are required for insulation. It is theorized that Mod(mdg4)-67.2 usually aids gene activation but can also act as a coinsulator by helping Su(Hw) trap facilitators of activation, such as the Chip protein (Gause, 2001).

This study found that certain loss-of-function alleles of mod(mdg4) reduce insulation by the Su(Hw) protein in the cut gene. This is evidence that mod(mdg4) products are not simply targets of Su(Hw) insulator activity but contribute to the insulator activity of Su(Hw). Wild-type Mod(mdg4)-67.2, the major protein product of mod(mdg4), interacts with a region of Su(Hw) that has been shown to be required for insulation in vivo, but the truncated versions of the Mod(mdg4)-67.2 proteins produced by the viable mod(mdg4)u1 and mod(mdg4)T6 alleles did not. This is consistent with the observation that binding of Mod(mdg4) proteins to Su(Hw) binding sites on salivary gland polytene chromosomes is greatly reduced in mod(mdg4)u1 mutants. mod(mdg4)u1 and mod(mdg4)T6 more strongly reduce insulator activity than do null alleles of mod(mdg4) and that this antimorphic nature of mod(mdg4)u1 may stem from the ability of the mutant protein to interact with wild-type Mod(mdg4)-67.2 protein. To explain these observations, a model is proposed in which a multimer of Mod(mdg4)-67.2 interacts with more than one Su(Hw) molecule to form the active insulator complex, and the truncated Mod(mdg4)-67.2 proteins produced by mod(mdg4)u1 and mod(mdg4)T6 destabilize this complex (Gause, 2001).

The evidence that Mod(mdg4)-67.2 is an active component of the gypsy insulator that blocks gene activation appears at first glance to be contradictory to the evidence indicating that the mod(mdg4) gene is a member of the trxG of genes that activate genes in the bithorax complex. Another trxG protein, however, also appears to have insulator activity. The GAGA factor encoded by the Trithorax-like (Trl) gene is similar to Mod(mdg4)-67.2 in that it contains a BTB/POZ motif at the N terminus, self-interacts, and supports activation of the bithorax complex. GAGA factor is also required for enhancer blocking by the insulator associated with the even-skipped promoter. This insulator activity requires GAGA binding sites just proximal to the transcription start site and is diminished by Trl mutations. Potential GAGA binding sites are found just proximal to many promoters in Drosophila, including sequences associated with insulator activity in the alpha1 tubulin gene promoter. The GAGA-dependent insulator just proximal to the eve promoter does not prevent activation of the eve promoter by upstream enhancers even though it is positioned between them. Indeed, GAGA binding sites just proximal to the engrailed gene promoter potentiate activation by an upstream enhancer. To resolve the paradoxical insulator and activator activities of the GAGA and Mod(mdg4)-67.2 BTB/POZ proteins, therefore, it must be theorized that the function of promoter-proximal insulators is to aid activation of the promoters that contain them by helping to capture and anchor distal activator or facilitator proteins near the promoter. If so, it is feasible that the Mod(mdg4)-67.2 protein has a promoter-anchoring function in the bithorax complex, but when bound to Su(Hw), it anchors activator or facilitator proteins far from the promoter, thereby preventing activation (Gause, 2001).

Combinatorial use of translational co-factors for cell type-specific regulation during neuronal morphogenesis in Drosophila: Nos and Pum regulate the expression of cut and head involution defective

The translational regulators Nanos (Nos) and Pumilio (Pum) work together to regulate the morphogenesis of dendritic arborization (da) neurons of the Drosophila larval peripheral nervous system. In contrast, Nos and Pum function in opposition to one another in the neuromuscular junction to regulate the morphogenesis and the electrophysiological properties of synaptic boutons. Neither the cellular functions of Nos and Pum nor their regulatory targets in neuronal morphogenesis are known. This study shows that Nos and Pum are required to maintain the dendritic complexity of da neurons during larval growth by promoting the outgrowth of new dendritic branches and the stabilization of existing dendritic branches, in part by regulating the expression of cut and head involution defective. Through an RNA interference screen a role was uncovered for the translational co-factor Brain Tumor (Brat) in dendrite morphogenesis of da neurons, and it was demonstrated that Nos, Pum, and Brat interact genetically to regulate dendrite morphogenesis. In the neuromuscular junction, Brat function is most likely specific for Pum in the presynaptic regulation of bouton morphogenesis. Thess results reveal how the combinatorial use of co-regulators like Nos, Pum and Brat can diversify their roles in post-transcriptional regulation of gene expression for neuronal morphogenesis (Olesnicky, 2012).

Post-transcriptional mechanisms of gene regulation such as translational control play a fundamental role in the development and function of the nervous system. Genetic studies have identified roles for the translational repressors Nos and Pum in sensory neuron and NMJ morphogenesis, NMJ function, and motor neuron excitability, and Pum has been implicated in long-term memory. Understanding the selectivity of these regulators for different mRNA targets is essential to identify the cellular processes they regulate for neuronal morphogenesis and neural function. This study shows that different combinations of Nos, Pum, and the co-factor Brat confer cell type-specific regulation during morphogenesis of Drosophila da sensory neurons and the NMJ (Olesnicky, 2012).

In Drosophila class IV da neurons, dendritic arbors grow rapidly during the first larval instar to establish nonredundant territories that cover the larval body wall. During the second and third larval instars, da neuron dendrites add and lengthen higher order branches to maintain body wall coverage as the larva undergoes dramatic growth. Results from live imaging analysis place the requirement for Nos and Pum during the third larval instar, indicating that Nos and Pum are not involved in the establishment of dendritic territories but rather in maintaining the density of terminal branches during late larval growth by promoting branch extension and preventing branch retraction. The possibility cannot be ruled that branch stabilization depends on Nos and Pum activity earlier during larval development. Evidence is provided that this maintenance function of Nos and Pum depends on their regulation of the proapoptotic protein Hid. Nos has previously been proposed to repress hid mRNA translation in developing germ cells to suppress apoptosis, although requirements for Pum and Brat were not tested. Together, these data showing that Hid is elevated in nos and pum mutant da neurons and that both the upregulation of Hid and the loss of terminal branches in nos mutants are suppressed by reduction of hid gene dosage suggest that repression of hid mRNA translation by Nos and Pum is also crucial for dendrite morphogenesis. Biochemical analysis will be required to test this model directly (Olesnicky, 2012).

In cultured Drosophila cells, Hid localizes to mitochondria and this localization is required for full caspase activation. By contrast, Hid protein is detected in the nucleus in nos and pum mutants. A similar nuclear accumulation has been proposed to sequester Hid in larval malphigian tubules and prevent apoptosis of this tissue during metamorphosis (Shukla, 2011). The nuclear accumulation of Hid may indeed explain why upregulation of Hid in nos and pum da mutants does not cause cell death. Nuclear Hid sequestration in nos and pum mutant neurons is also consistent with the apparent absence of activated caspase. How Hid causes dendrite loss in nos and pum mutant neurons remains to be determined but could involve activation of a pathway similar to injury induced dendrite degeneration, which resembles pruning but is caspase-independent (Olesnicky, 2012).

Nos and Pum were initially identified because of their role in translational repression of hb mRNA in the posterior region of the early embryo. There, the two proteins form an obligate repression complex, with Pum conferring the RNA-binding specificity and Nos, which is synthesized only at the posterior pole of the embryo, providing the spatial specificity. More recent studies have shown that Nos and Pum are not obligate partners, however. In the ovary, Pum functions together with Nos in germline stem cells to promote their self-renewal, while Pum acts independently of Nos in progeny cystoblasts to promote their differentiation (Harris, 2011). In the NMJ, Pum and Nos work in opposition to one another to regulate both morphological and electrophysiological characteristics of synaptic boutons. While Hid levels are similarly elevated in nos and pum mutant da neurons, the differential effects on cut expression observed in the two mutants suggest that in addition to working together, Nos and Pum participate in separate complexes that target different mRNAs even within the same cell type. Presumably, additional factors that associate selectively with Nos or Pum drive the formation of distinct complexes with different binding specificities. Pum represses eIF4E translation in the post-synaptic NMJ independently of Nos, suggesting that some of Pum's effects in da neurons could be through more global effects on translation (Olesnicky, 2012).

A third cofactor, Brat, is required for Nos/Pum-dependent repression of hb mRNA in the early embryo and paralytic mRNA in motorneurons. However, Brat is not required for Nos/Pum-mediated repression of cyclin B mRNA in primordial germ cells or for Nos/Pum function in germline stem-cell maintenance. Structural and molecular analyses have shown that Brat is recruited to the Nos/Pum/NRE ternary complexes through an interaction between its conserved NHL (NCL-1, HT2A, and LIN-41) domain and Pum. The Brat NHL domain also mediates interaction of Brat with the eIF4E-binding protein d4EHP and mutations in Brat that abrogate this interaction partially disrupt translational repression of hb, suggesting a mechanism by which the Pum/Nos/Brat/NRE complex could repress cap-dependent initiation. The results indicate that Brat also collaborates with Nos and Pum to regulate dendrite morphogenesis by a mechanism involving d4EHP interaction and that this requirement is cell type-specific. While genetic analysis suggests that Brat is required for Nos/Pum-mediated regulation of dendrite complexity and Hid expression in class IV da neurons, it is dispensible for Nos and Pum functions in class III da neurons. A similar cell type-specific requirement for Brat function in Nos/Pum-mediated repression within the CNS has been proposed based on the ability of brat mutants to counteract repression of paralytic mRNA due to Pum overexpression. Since Brat is expressed throughout the dorsal cluster of larval sensory neurons and CNS, it is unclear whether the recruitment of Brat to the complex occurs only in certain cell types or whether its function in the complex is target dependent. In contrast to nos and pum mutants, however, brat mutants have no effect on cut expression, suggesting that Brat's role in translational regulation is in fact limited to a subset of Nos/Pum-dependent processes (Olesnicky, 2012).

The findings that Brat functions presynaptically in bouton formation and that brat and pum mutant NMJs exhibit similar defects in bouton formation suggest that Brat is selectively recruited by Pum, but not by Nos, to regulate distinct target mRNAs in bouton development. Similarly, Brat functions selectively with Pum in ovarian cystoblasts to promote differentiation, suggesting that a Pum/Nos/NRE ternary complex is not essential for recruitment of Brat. Pum and many of its homologs in other organisms, members of the large Puf (Pum/FBF) protein family, typically recognize sequences that contain a core UGUA motif, although features beyond the core element also influence target mRNA recognition. Pum has been shown to also recognize a UGUG motif that is found in binding sites for the C. elegans Puf protein FBF (Menon, 2009). Thus, it is possible that the interaction of Pum with different binding sites dictates the assembly of the particular repression complex. Interactors like Brat might add an additional layer of regulation by altering the specificity or affinity of Pum for particular targets, thereby generating diverse cellular and morphological outputs within a particular cell type (Olesnicky, 2012).

Transcriptional regulation

Continued: part 2/3 part 3/3

cut: Biological Overview | Evolutionary Homologs | Targets of Activity | Developmental Biology | Effects of Mutation | References

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